Only one-quarter of patients show an adequate clinical prophylactic response in double-blind, randomized, one-year trials of lithium or carbamazepine monotherapy. Even with the combination of lithium and carbamazepine, only 50% of non-selected, high functioning outpatients respond. With the additional use of valproate, 40% of patients still remain unresponsive. It is from this larger pool of treatment-refractory patients that the inpatient unit seeks to better understand the differential pathophysiological pathways to recurrent unipolar and bipolar affective disorders and develop new therapeutic modalities. Since existing treatments often require protracted clinical trials in order to assess efficacy, we are also pursuing treatments with more rapid onsets of action (sleep deprivation and thyrotropin-releasing hormone [TRH]) and attempting to establish clinical and neurobiological markers and predictors of clinical responsivity. A double-blind, randomized trial of T3 versus TRH versus placebo augmentation of venlafaxine is examining relative rapidity of antidepressant onset in outpatients. In relationship to predictors, preliminary evidence indicates that patients with depression in the context of global hypermetabolism on PET and regional increased metabolism in left insula and temporal areas are more likely to be responsive to carbamazepine (N = 26), while those with the more classic pattern of frontal hypometabolism are more likely to be responsive to the novel calcium channel blocker nimodipine. We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and that those with lower CSF somatostatin at baseline tend to be more likely to respond clinically to these nimodipine-induced increases. A major inpatient study involves a double-blind, randomized trial of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin), versus one that decreases excitatory glutamatergic function (lamotrigine), versus placebo, with patients crossing over to the other drug treatment in order to ascertain differential clinical response. Preliminary data are highly promising in our treatment-refractory patients with an overall 39% response rate to gabapentin and 50% response rate to lamotrigine, but with only an 8% response rate to the placebo phase. Preliminary evidence suggests that baseline patterns of hypoperfusion on PET, as assessed with 015 water, are associated with clinical response to these agents. The major new treatment development in the Branch, which is proceeding in both inpatient and outpatient clinical trials, is the use of repeated transcranial magnetic stimulation (rTMS) of the brain. The initial paradigms for exploring antidepressant effects were developed in this Branch. Two of the first six patients responded in open studies and then a double-blind, randomized, crossover trial indicated significant antidepressant effects of active rTMS for two weeks compared with the sham manipulation in a study now in press in the Am J Psychiatry. The next completed study focused on the differential responsivity of low-frequency (1 Hz) versus higher frequencies (20 Hz) stimulation over left frontal cortex at 80% of motor threshold. The data in the first 15 subjects suggest differential response within the same patient to these different frequencies. Those with a pattern of baseline hypometabolism tend to be responsive to the 20 Hz stimulation in association with normalization of their glucose utilization, while those with baseline patterns of hypermetabolism are more likely to respond to the 1 Hz stimulation, which induces relative hypometabolism and normalization of glucose utilization compared with controls. As the incidence and magnitude of clinical responsivity was not adequate for many patients in this third study, the trial has now entered a new phase of parametric study with the use of higher intensities (100% of motor threshold) and initial results appear to be demonstrating a higher response rate with this modification. Two studies in normal volunteers confirm that 1 Hz rTMS over either motor or frontal cortex induces relative decrements in frontal metabolism on PET. Thus, a number of promising and mechanistically novel treatment approaches have been pioneered in the Branch and additional effort will be aimed at defining optimal parameters of response the elucidation of clinical and neurobiological markers of such response. This and related work on the development of new treatment approaches for refractory bipolar patients is also being pursued on a wider basis with the establishment of the first NIMH-Stanley Foundation-supported Bipolar Treatment Outcome Network with multiple sites in the U.S. and one in Europe. This clinical trials network addresses most of the recommendations of the NIMH 1989 and 1994 meetings on bipolar illness.